JPS6251681A - Physiologically active substance sen-366 and production thereof - Google Patents

Abstract

NEW MATERIAL:SEN-366 of formula (n is 0 or 1; dotted line represents single or double bond). USE:It has platelet aggregation inhibiting activity and is useful as a remedy for thrombosis or an agent for suppressing metastasis of cancer, etc. PREPARATION:The compound of formula I can be produced by the direct dehydration reaction of the compound of formula II. For example, 1mol of the compound of formula II is made to react with pyridine and 1,2-3mol of phthalic anhydride at 50-100 deg.C, preferably 70-80 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a physiologically active substance called 5EN-366 useful as a pharmaceutical and a method for producing the same. More specifically, the present invention is directed to the following general formula (1) [where n does not represent 0 or 1, and -= represents a -m bond or a double bond. ] The present invention relates to a physiologically active substance called 5EN-366 represented by: and a method for producing the same.

(Prior Art) In recent years, pharyngeal diseases have come to occupy a large part of medical treatment, both in terms of their morbidity and the difficulty of treatment. In particular, patients with acute myocardial infarction, thrombo-occlusive vasculitis, arteriosclerosis obliterans, chronic glomerulonephritis, nephrotic syndrome, cerebral arteriosclerosis, sequelae of cerebral thrombosis, angina pectoris, patients undergoing surgery, and patients undergoing dialysis for more than one month Chronic renal failure, short-term local anemia, and thrombosis such as blood clots in patients using prosthetic devices W (artificial heart, artificial kidney, etc.) are becoming problematic as adult diseases. For these thromboses, attempts have been made to administer platelet aggregation inhibitors for the purpose of thrombosis prevention and treatment. , ticlopidine is commonly used.

Furthermore, it has been confirmed that platelet aggregation inhibitors have a wide range of usefulness as pharmaceuticals, such as being expected to be substances that inhibit cancer metastasis.

The compound of the present invention can also be used as a raw material for producing anthracycline compounds, which are antitumor agents.

On the other hand, several types of platelet aggregation inhibitors derived from microorganisms are already known, and research on their usefulness as medicines is underway.

For example, WF-5 from 8 supergillus Hz
239 (The Journal of Antibfo
tics Vol, 37 Nn5 469-474) and 5EN-12 from Streptomyces sp.
8-B (Japanese Unexamined Patent Publication No. 59-095893).

(Problems to be Solved by the Invention) However, the above-mentioned platelet aggregation inhibitors have certain limitations in their effectiveness, and there is no solid evidence that their safety is necessarily satisfactory.

The present inventors have been conducting research to develop a platelet aggregation inhibitor that is more effective than the existing drugs mentioned above and is more useful in terms of safety. The inventors have already applied for a patent after discovering that there is a series of substances that are unrelated in terms of their chemical structure and are superior in terms of effectiveness and safety. In the process of continuing research on the compounds related to the patent application, we have arrived at a group of compounds that have pharmacological effects equal to or superior to those mentioned above, and have completed the present invention.Therefore, the purpose of the present invention is to achieve the goals of the above patent application. Similarly, the aim is to develop a new drug that is significantly superior to the existing platelet aggregation inhibitors.

(Means for Solving the Problems) The novel physiologically active substance according to the present invention has the following general formula [11] [wherein n does not represent 0 or 1]. = represents a -m bond or a double bond. ] can be obtained by dehydrating a compound represented by the following.

The compound represented by the general formula (n) has α- and β-anomers depending on its steric configuration, and both can be expressed by the general formula (1) according to the present invention by the method detailed below. can be induced into compounds.

These compounds are referred to herein as 5EN-366.

The compound represented by the general formula (1) has low toxicity and a strong ability to produce platelet aggregation 1ηl. That is, as detailed below as a biological property, adenosine-5'-
Significantly inhibits platelet aggregation in domestic rabbits using diphosphorus fl (ADP), arachidonic acid (AA), or collagen as a platelet aggregation-inducing substance. Therefore, these substances are useful as medicaments for the treatment and prevention of the aforementioned thrombosis.

The compound represented by the general formula [■] was obtained for the first time by the present inventors, and is a new compound that has not been described in any literature. Patent issued (Patent application 1982-2227)
No. 40 and others). The present invention is directly related to these inventions.

The compound represented by the general formula (1) according to the present invention can be obtained by directly subjecting the compound (n) to a dehydration reaction.

For example, it can be obtained by subjecting compound (n) to a heating reaction with pyridine and phthalic anhydride.

The physicochemical properties of representative substances of the present invention are described in Examples. Furthermore, the biological properties of the representative substance of the present invention are as follows.

<Platelet aggregation inhibitory effect> (1) Materials and methods The specimen is used after being dissolved in dimethyl sulfoxide. The final concentration of solvent is adjusted to 1%.

Dimethyl sulfoxide at the same concentration was used as a control.

ADP at a final concentration of 5 μh as a platelet aggregation-inducing substance, 1
50. II (7) AA (7rah!-F 7%ri,
And 10 μg/ml collagen was used.

(2) Ill production of platelets Blood was collected from the arterial artery of a male rabbit weighing 2.0 to 2.5 kg, 1/10 volume of 3.8% trisodium citrate was added to the blood, mixed gently, and the mixture was heated at 1300 x The supernatant obtained by centrifugation at 1600 x g for 2 minutes was used as platelet-rich plasma (hereinafter referred to as "PRPJ"). Plasma (rP)
PPJ).

(3) Method for measuring aggregation ability A platelet aggregation meter was used to record changes in absorbance over time due to platelet aggregation.

That is, 200 μl of PPP was taken and the difference from PPP was adjusted to a constant value, and then 25 pl of a control solvent or sample was added to the PPP and stirred at 11,000 rpm. After 1 minute, 25 μl of an agglutination-inducing substance was added and the change in absorbance was recorded.

The inhibition rate was determined from the maximum agglutination rate (A%) of the control and the maximum agglutination rate (B%) of the specimen according to the following formula.

Inhibition rate (%) - (,1-B/A) Test results of representative compounds according to the present invention are shown in Table 1.

As shown above, the compound of the present invention has an important biological property of inhibiting platelet aggregation, and is useful as a therapeutic agent for thrombosis, etc., an agent for suppressing cancer metastasis, and the like.

When administering the compound of the present invention as a medicine to patients with thrombosis, the compound of the present invention may be administered as is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, at a concentration of 0.1% to 99.5%.
%, preferably 0.5% to 90%, to animals including humans.

As carriers, one or more solid, semisolid, or liquid diluents, fillers, and other formulation auxiliaries are used.

The pharmaceutical composition of the present invention is preferably administered in a dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intratissueally, locally, transdermally, etc., or rectally. Of course, it can be administered in dosage forms suitable for these administration methods, such as tablets, granules, powders, capsules, injections, suppositories, etc.For example, in the case of oral administration, enteric-coated tablets or capsules are used. is particularly preferred.

It is desirable to adjust the dose of the platelet aggregation inhibitor in consideration of the patient's condition such as age, weight, route of administration, nature and severity of the disease, etc. The amount of active ingredient is 0.1 to 100 per day.
A range of 0 mg is common.

In some cases, a lower dose than this may be sufficient, and in other cases, a higher dose may be required. When administering a large amount, it is desirable to divide the dose into several times a day.

(Example) The present invention will be specifically explained below with reference to Examples, but the present invention is not limited thereto.

Example 1 Compound 1 in which - is a single bond and n is 1 in general formula (n)
Dissolve g in pyridine 3+11 and add phthalic anhydride 75(b
Add ag and stir at 70-80°C for 3 hours. After the reaction is complete, add 50 ml of water and extract twice with 50 ml of ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. Residue 910++
+g was subjected to silica gel column chromatography (Wakogel C-300), and n-hexane/ethyl acetate (2
:1) and recrystallized from ether to give the general formula (1).
), where = is a single bond and n is 1, 265 mg
Obtained.

Optical rotation [α)'t: --242,83 (c = 0.6
91 ClICl3) m, p, 86-87°C (colorless crystals) Rf O, 72 Thin layer chromatography (Kieselgel 60P254
) The developing solvent is ethyl acetate 20-hexane-181 elemental analysis value CI8 Calculated value as H280B (%') C
: 63.51 H: 8.29 Actual value (%) C
: 63.38 H: 8.40 Example 2 - 500 mg of a compound of formula (II) where = is a double bond and n is 1 is dissolved in 2 ml of pyridine, 375 mg of phthalic anhydride is added, and the mixture is heated at 70 to 80°C. Stir for 3 hours.

After the reaction is complete, add 5 ml of water and extract twice with 50 ml of ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure.

470+++ g of the residue was subjected to silica gel column chromatography (Wako Gel C-300), eluted with n-hexane/ethyl acetate (2: l), and recrystallized from ether. 55 mg of a compound in which n is 1 was obtained.

Optical rotation [α Liao - 46.82 (c = 0.615 C
lICl3) R, p, 113-115°C (colorless crystal) Rf Q, 76 Thin layer chromatography (Kieselgel 601725
4) The developing solvent is ethyl acetate 20-hexane = 1:1 elemental analysis value calculated as CIll H2@06 (%)
C: 63.88 H: 7.74 Actual value (%)
C: 63.61 H; 7.82 Example 3 11l1 In formula (II), = single bond and n is 0, 1 g of the compound is dissolved in 2 ml of pyridine, and phthalic anhydride 60
Add 0+sg and stir at 70-80°C for 3 hours. After the reaction was completed, 5Qml of water was added, and the solution was diluted with 50ml of ethyl acetate.
Extract times. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. residue 760
mg was subjected to silica gel column chromatography (Wako Gel C-300), and n-hexane/ethyl acetate (2
: 180 mgfG of the compound in which - is a single bond and n is 0 in the -1 role formula (1) is eluted with 1).

Optical rotation [α) 8 = -241,41 (c = 1.01
9 cnct3) Oil Rf O,75 Thin layer chromatography (Kieselgel 60F25/
I) The developing solvent is ethyl acetate 20-hexane-181 elemental analysis value calculated as CI281804 (%') C: 63.70 H: 8.0
2 Actual measurement value (%) C: 63.84), I:
7.93 Procedural Amendment M (Method)

Claims (2)

[Claims] (1) The following general formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, n represents 0 or 1. ■ represents a single bond or a double bond. ] A physiologically active substance called SEN-366 represented by: (2) The following general formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] [In the formula, n represents 0 or 1. ■ represents a single bond or a double bond. ] The following general formula [I] is characterized by subjecting the compound represented by [I] to a dehydration reaction. ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, n represents 0 or 1. ■ represents a single bond or a double bond. ] A method for producing a physiologically active substance called SEN-366 represented by: